Preparation and application of novel pyrimidine KRAS G12C inhibitor

Abstract

The invention discloses a novel pyrimidine KRAS-G12C inhibitor as well as a preparation method and application of the novel pyrimidine KRAS-G12C inhibitor. The pyrimidine compound disclosed by the invention has a remarkable inhibition effect on non-small cell lung cancer cells (NCI-H23 and NCI-H358) with high expression of KRAS-G12C, is particularly used as a medicine for treating and / or preventing the non-small cell lung cancer, is simple and efficient in preparation route, and has a good antitumor medicine development and application prospect.

Description

Technical Field

[0001] This invention relates to the fields of organic chemistry and medicinal chemistry, specifically to a novel pyrimidine KRAS G12C inhibitor and its preparation and application. Such compounds and their pharmaceutically acceptable salts can be used for the treatment and prevention of various cancers with KRAS G12C mutations. Background Technology

[0002] Mutations in NRAS, HRAS, and KRAS2 within the rat sarcoma gene (RAS) family are common cancer-related gene mutations. KRAS, as the most common subtype of the RAS proto-oncogene, is a common driver gene for solid tumors such as lung cancer, pancreatic cancer, and colon cancer. After a KRAS gene mutation, the KRAS protein continuously binds to GTP, leading to its persistent activation and overactivation of downstream signaling pathways, inducing the occurrence and development of malignant tumors. Clinical data indicate that KRAS mutations are primarily found in solid tumors such as colorectal cancer (CRC, US: 45%, China: 49%), pancreatic cancer (PCA, US: 90%, China: 87%), and non-small cell lung cancer (NSCLC, US: 35%, China: 13%). Among various KRAS mutations, G12 mutation is the most common, with G12C mutation being the most prevalent in non-small cell lung cancer. For the first thirty years after KRAS was discovered in 1982, it was considered an "untreatable" target due to the lack of a suitable "pocket" for drug binding. Cancers with KRAS mutations could only be inhibited by inhibitors of related signaling pathways. This changed in 2013 when the Shokat group discovered the Switch-II allosteric pocket and proposed a covalent binding strategy. Based on this, Amgen developed ARS-1620, the first KRAS G12C inhibitor with in vivo activity. Since 2021, Amgen has developed five more KRAS G12C inhibitors based on ARS-1620: AMG-510 (sotorasirb), MRTX-849 (adagraxirb), fluzole, gorsorexate, and glerexalate. Meanwhile, other targeted drugs targeting KRAS G12C mutations (such as JDQ443, GDC-6036, IBI-351, and JAB-21822) are undergoing clinical trials.

[0003] The number of patients with KRAS-G12C mutations in non-small cell lung cancer is comparable to that of those with EGFR mutations, but currently available drugs offer insufficient monotherapy efficacy. Furthermore, most reported KRAS-G12C inhibitors have a bicyclic hinge region, unlike previous reports. This invention discovers a novel class of monocyclic pyrimidine compounds that exhibit potent inhibitory activity against KRAS-G12C protein and its mutant cells. In terms of preparation, this invention allows for the efficient synthesis of key intermediates and target compounds using a simple method. Summary of the Invention

[0004] The technical problem solved by this invention is to provide a pyrimidine derivative as a KRAS-G12C inhibitor.

[0005] This invention provides compounds with the structural formula shown in Formula I or pharmaceutically acceptable salts thereof:

[0006]

[0007] in:

[0008] R 1 Selected from hydrogen, C 1-6 Alkyl, halogen, or cyano groups;

[0009] R 2 Selected from hydrogen, C 3-6 Heterocyclic group, C 3-6 Heterocyclic alkyloxy or C 3-6 Heterocyclic alkyl nitrogen groups;

[0010] Ring L is a saturated or partially saturated monocyclic, bridged, or spirocyclic ring of 4-12 atoms, wherein the saturated or partially saturated monocyclic ring may optionally be additionally bounded by one or more R atoms. 3 Replace, where R 3 Selected from: hydrogen, cyano, C 1-6 Alkyl, C 1-6 Alkoxy or C 3-6 cycloalkyl;

[0011] Ar is selected from C 6-10 Aryl or C 5-10 Mixed aromatics;

[0012] R 4 Selected from C 1-4 alkenyl, C 1-6 Haloalkyl, C 5-10 heteroaryl or C 3-6 Halogenated cycloalkyl groups;

[0013] In an embodiment of the present invention, R 1 Selected from hydrogen, methyl, and cyano groups;

[0014] In a further preferred embodiment of the present invention, R1 The preferred groups are methyl and cyano groups.

[0015] In an embodiment of the present invention, R 2 Selected from hydrogen or C 5-6 Heterocyclic alkyloxy groups;

[0016] In a further preferred embodiment of the present invention, R 2 Selected from (S)-2-(1-oxo)methyl)-N-methylpyrrolidinyl or (2S,7aR)-7a-((1-oxo)methyl))-2-fluorohexahydro-1H-pyrrolidinyl;

[0017] In embodiments of the present invention, the ring L is selected from piperazine, monosubstituted piperazine, polysubstituted piperazine, spirocyclic ring, etc. In a further preferred embodiment of the present invention, the R of ring L... 3 Methyl is preferred.

[0018] In an embodiment of the present invention, Ar is selected from C. 6-10 Aryl or C 5-10 A heteroaryl group, wherein the heteroaryl group contains 1-3 heteroatoms selected from N or O;

[0019] In a further preferred embodiment of the present invention, Ar is phenyl, 2-fluoro-4-nitrophenyl, 2-fluoro-4-cyanophenyl, 2,6-dimethylphenyl, 4-chlorophenyl, 2-fluoro-6-methoxyphenyl, 1-naphthyl or 1-(4-chlorophenyl)pyrazolyl-3.

[0020] In an embodiment of the present invention, R 4 Selected from C 1-4 alkenyl, C 1-6 Haloalkyl, C 5-10 heteroaryl or C 3-6 Halogenated cycloalkyl groups;

[0021] In a further preferred embodiment of the present invention, R 4 It is vinyl or chloromethyl.

[0022] In the most preferred embodiment of the present invention, the following specific compounds are included:

[0023]

[0024] In many cases, the compounds of the present invention are capable of forming acidic and / or basic salts due to the presence of piperazine groups or similar groups.

[0025] The beneficial effects of this invention are: the pyrimidine antitumor compounds and their pharmaceutically acceptable salts obtained by this invention have excellent antitumor activity and safety, and can be used to treat cancers such as non-small cell lung cancer and pancreatic cancer containing KRAS-G12C mutations. Detailed Implementation

[0026] The examples and preparation methods provided below further illustrate and demonstrate the compounds of the present invention and their preparation methods. It should be understood that the scope of the following examples and preparation methods does not limit the scope of the present invention in any way.

[0027] The following synthetic routes describe the preparation of the Formula I derivatives of this invention. All starting materials were prepared by methods well known to those skilled in the art of organic chemistry, or are commercially available, as described in the following synthetic routes. All final derivatives of this invention were prepared by methods described in the following synthetic routes or by similar methods well known to those skilled in the art of organic chemistry. The substituents R in all compounds in the routes are... 1 R 2 R 3 R 4 R 5 Or Ar as defined in the claims. The synthetic route is as follows:

[0028] Synthesis Scheme 1

[0029]

[0030] The steps for Option 1 are as follows:

[0031] Compound A1 was reacted with substituted piperazine and other heterocyclic compounds via nucleophilic substitution to give compound A2; then A2 was coupled with Suzuki to give A3; finally, A3 was deprotected by the Boc group and reacted with acryloyl chloride, chloroacetyl chloride and other compounds via acylation to give the target compound A5.

[0032] Synthesis Scheme 2

[0033]

[0034] The steps for Option 2 are as follows:

[0035] Using compound B1 as a starting material, compound B4 was obtained by sequentially undergoing nucleophilic substitution, Suzuki coupling, and oxidation reactions. Subsequently, B4 underwent nucleophilic substitution and deBoc reactions to obtain compound B6. Finally, B6 underwent amidation to obtain the target compound B7.

[0036]

[0037] The steps for Option 3 are as follows:

[0038] Using compound B2 as a starting material, compound C2 was obtained by sequentially undergoing deprotection and amidation reactions; subsequently, compound C5 was obtained by oxidation, nucleophilic substitution, and Suzuki coupling reactions of C2.

[0039] The following specific examples are of compounds 1-10 above, where examples 1-2 follow route 1, examples 3-8 follow route 2, and examples 9-10 follow route 3. Examples are as follows:

[0040] Example 1: 1-(4-(6-(2-fluoro-6-hydroxyphenyl)-5-methylpyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (1)

[0041] Intermediate 4,6-dichloro-5-methylpyrimidine (500 mg, 3.07 mmol, 1.0 eq.) and triethylamine (0.43 mL, 2.0 eq.) were added to dichloromethane, cooled to -20 °C, and N-Boc-piperazine (571 mg, 3.07 mmol, 1.0 eq.) was slowly added. The reaction was carried out at 0 °C for 2 h. The reaction was stopped, purified water was added to dilute the reaction solution, and the mixture was extracted with dichloromethane. The organic phases were combined, washed once with water and once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give tert-butyl-4-(6-chloro-5-methylpyrimidine-4-yl)piperazine-1-carboxylic acid ester, which was a light yellow solid product with a yield of 70%. 1 H NMR (400MHz, Chloroform-d) δ8.40(s,1H),3.54–3.52(m,4H),3.38–3.35(m,4H),2.27(s,3H),1.49(s,9H).

[0042] Intermediate tert-butyl-4-(6-chloro-5-methylpyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 0.96 mmol, 1.0 eq), 2-fluoro-6-methoxyphenylboronic acid (407 mg, 2.39 mmol, 2.5 eq.), and sodium carbonate solid (305 mg, 2.88 mmol, 3.0 eq.) were dissolved in a mixed solution of 1,4-dioxane and purified water (10 mL, v / v, 4:1). Under nitrogen protection, tetrakis(triphenylphosphine)palladium (111 mg, 0.096 mmol, 0.1 eq) was added, and the mixture was reacted at 100 °C for 5 hours. The mixture was filtered, the reaction solution was evaporated to dryness, and purified by column chromatography to give intermediate tert-butyl-4-(6-(2-fluoro-6-methoxyphenyl)-5-methylpyrimidin-4-yl)piperazine-1-carboxylate, 94 mg white solid, yield 56%. 1 H NMR(400MHz,Chloroform-d)δ8.49(s,1H),7.46–7.37(m,1H),7.10–6.92(m,2H),

[0043] 6.87–6.75(m,1H),3.54–3.52(m,4H),3.38–3.35(m,4H),2.27(s,3H),1.49(s,9H).

[0044] The intermediate tert-butyl-4-(6-(2-fluoro-6-methoxyphenyl)-5-methylpyrimidin-4-yl)piperazine-1-carboxylic acid ester (200 mg, 0.50 mmol, 1.0 eq) was dissolved in dichloromethane solution, and trifluoroacetic acid (0.93 mL, 12.5 mmol, 25 e.q.) was added. The reaction was carried out at 25 °C for 0.5 h. The reaction solution was extracted with dichloromethane and concentrated under reduced pressure to obtain a yellow oily substance. No purification was required. The product, calculated as 120 mg (80% of the theoretical yield), was directly used for the next reaction.

[0045] The obtained oily substance was dissolved in dichloromethane, and triethylamine (0.17 mL, 3 e.q.) was added. The temperature was lowered to -70 °C, and acryloyl chloride (40 mg, 0.44 mmol, 1.1 eq) was added dropwise. The reaction was maintained at -70 °C for 20 minutes. The mixture was extracted with dichloromethane, and the organic phase was washed once each with purified water and saturated brine. The mixture was dried over anhydrous sodium sulfate and evaporated to dryness to obtain a crude yellow oily substance. The crude product was purified by column chromatography (PE / EA = 4:1) to give a white solid compound 1-(4-(6-(2-fluoro-6-hydroxyphenyl)-5-methylpyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one. 1 H NMR(600MHz,DMSO-d6)δ8.62(s,1H),7.55–7.41(m,1H),7.10–6.92(m,2H),6.90–6.79(m,1H),6 .16(d,J=16.8Hz,1H),5.73(d,J=10.2Hz,1H),3.75–3.73(m,7H),3.40(s,4H),1.95(s,3H).13C NMR (150MHz, DMSO) δ165.5,164.9,160.6,159.4,157.9,155.2,131.3,128.6,128 .1,119.1,116.2,108.3,108.0,56.6,48.6,48.2,45.3,41.7,15.4.HRMS(ESI)m / z calculated for C 19 H 21 FN4O2[M+H] + 357.1721, found 357.1718.

[0046] Example 2: 1-(4-(6-(2-fluoro-6-hydroxyphenyl)-5-methylpyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (2)

[0047] Compound 1-(4-(6-(2-fluoro-6-hydroxyphenyl)-5-methylpyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (80 mg, 0.20 mmol) was dissolved in dichloromethane, cooled to -78°C, and boron tribromide (113 mg, 2.00 mmol) was added. The mixture was then heated to room temperature and reacted for 2 hours. After the reaction was complete, the temperature was lowered to -30°C, and saturated sodium bicarbonate aqueous solution was slowly added to adjust the pH of the reaction solution to approximately 8. The reaction solution was extracted with dichloromethane, and the organic phase was separated. The organic phase was washed once with saturated brine, dried over anhydrous sodium sulfate, and purified by column chromatography to obtain 1-(4-(6-(2-fluoro-6-hydroxyphenyl)-5-methylpyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one, a white solid, 35 mg, yield: 51%. 1 H NMR(600MHz,Chloroform-d)δ8.64(s,1H),7.30(q,J=7.8Hz,1H),6.87(d,J=8.2Hz,1H),6.74–6.67(m,1H),6.62(dd,J =16.8,10.4Hz,1H),6.42–6.33(m,1H),5.80–5.75(m,1H),3.85–3.74(m,4H),3.60–3.57(m,4H),2.17(d,J=5.4Hz,3H); 13 CNMR (150MHz, CDCl3) δ166.6,165.7,159.7,158.9,158.2,153.9,132.0,128.6, 127.2,118.2,113.4,110.8,106.9,65.9,48.1,45.6,41.8,16.9; HRMS(ESI)m / z calculated forC 18 H 19 FN4O2[M+H] + 343.1564, found 343.1573.

[0048] Example 3: (S)-4-(4-(2-chloroacetyl)piperazin-1-yl)-6-(4-cyano-2-fluorophenyl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidin-5-carboxynitrile (3)

[0049] Intermediate 4,6-dichloro-5-cyano-2-methylthiopyrimidine (800 mg, 4.10 mmol, 1.0 eq.) and N-Boc piperazine (801 mg, 4.31 mmol, 1.05 eq.) were added sequentially to dry dichloromethane (25 mL), and the mixture was cooled to 0 °C. Triethylamine (829 mg, 8.21 mmol, 2.0 eq.) was slowly added, and the reaction was carried out at room temperature for 2 h. The mixture was then cooled to 0 °C, the pH was adjusted to neutral with 1 M HCl aqueous solution, and the mixture was extracted with dichloromethane. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give tert-butyl 4-(6-chloro-5-cyano-2-(methylthio)pyrimidin-4-yl)piperazine-1-carboxylate, a white solid product in 95% yield. 1 H NMR (400MHz, Chloroform-d) δ4.16–3.73(m,8H),2.51(s,3H),2.23(s,2H),1.45(s,9H).

[0050] Intermediate 4-(6-chloro-5-cyano-2-(methylthio)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (400 mg, 1.08 mmol, 1.0 eq), (4-cyano-2-fluorophenyl)boronic acid (446 mg, 2.7 mmol, 2.5 eq), and sodium carbonate solid (343 mg, 3.24 mmol, 3.0 eq) were dissolved in a mixed solution of 1,4-dioxane and purified water (10 mL, v / v 4:1). Under nitrogen protection, tetrakis(triphenylphosphine)palladium (125 mg, 0.108 mmol, 0.1 eq) was added, and the mixture was heated to 100 °C and reacted for 4 hours. The mixture was filtered, the reaction solution was evaporated to dryness, and purified by column chromatography to give 94 mg of white solid, yield 56%. 1 H NMR(400MHz,Chloroform-d)δ7.69(t,J=7.4Hz,1H),7.59(dd,J=8.0,1.6Hz,1H),7.52( dd,J=9.2,1.6Hz,1H),4.07–3.92(m,4H),3.70–3.51(m,4H),2.54(s,3H),1.49(s,9H).

[0051] The intermediate tert-butyl 4-(5-cyano-6-(4-cyano-2-fluorophenyl)-2-(methylthio)pyrimidin-4-yl)piperazine-1-carboxylate (300 mg, 0.66 mmol, 1.0 eq) was dissolved in dichloromethane and cooled to -30 °C. m-chloroperoxybenzoic acid (mCPBA, 342 mg, 1.98 mmol, 3.0 eq) was added, and the mixture was reacted at -20 °C for 30 minutes. After the reaction was complete, 20 mL of ice water was added, and the reaction solution was extracted with dichloromethane. The organic phases were combined, washed once with salt, dried over anhydrous sodium sulfate, and evaporated to dryness to give tert-butyl 4-(5-cyano-6-(4-cyano-2-fluorophenyl)-2-(methanesulfonyl)pyrimidin-4-yl)piperazine-1-carboxylate, a white solid, in 87% yield. 1 H NMR (400MHz, Chloroform-d) δ7.75 (q, J=6.9, 6.3Hz, 1H), 7.64 (dd, J=8.1, 1.4Hz, 1H), 7.5 7(dd,J=9.4,1.4Hz,1H),4.20–4.08(m,4H),3.76–3.56(m,4H),3.32(s,3H),1.50(s,9H).

[0052] Intermediate 4-(5-cyano-6-(4-cyano-2-fluorophenyl)-2-(methanesulfonyl)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (240 mg, 0.49 mmol, 1.0 eq) was added to dry tetrahydrofuran (5 mL), cooled to -10 °C, and sodium hydride solid (118 mg, 2.94 mmol, 60%, 6.0 eq) was slowly added. The mixture was cooled to -78 °C, and (S)-(-)-1-methyl-2-pyrrolidineethanol (170 mg, 1.47 mmol, 3.0 eq) was added. The mixture was then dissolved in 1 M solution at -30 °C. The pH was adjusted to neutral with aqueous HCl solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give (S)-4-(5-cyano-6-(4-cyano-2-fluorophenyl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, a white solid, yield: 40%. 1H NMR(400MHz,Chloroform-d)δ7.74(q,J=6.9,6.3Hz,1H),7.65(dd,J=8.1,1.4Hz,1H),7.57(dd,J=9.4,1.4Hz,1H),5.40(s,1H)4.82(d,J=3.8Hz, 1H),4.58(dd,J=12.6,3.6Hz,1H),4.20–4.08(m,4H),3.76–3.56(m,6H), 3.12(s,3H),2.42(d,J=10.2Hz,2H),2.12(d,J=8.2Hz,2H),1.48(s,9H).

[0053] (S)-4-(5-cyano-6-(4-cyano-2-fluorophenyl)-2-((1-methylpyrrolidin-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.96 mmol, 1.0 eq) was dissolved in dichloromethane (2.3 mL), and trifluoroacetic acid (0.7 mL, 9.25 mmol, 25 e.q.) was added at room temperature. The reaction was carried out at 25 °C for 30 min. 20 mL of dichloromethane was added to dilute the reaction solution, and the solution was concentrated under reduced pressure to obtain a yellow oil. No purification was required. The product was taken as 130 mg (80% of the theoretical yield) and directly used for the next reaction. The obtained oily substance was added to a dichloromethane solution (5 mL), followed by triethylamine (0.09 mL, 2.0 eq). The temperature was lowered to -70 °C, and chloroacetyl chloride (38 mg, 0.33 mmol, 1.07 eq) was added dropwise. The mixture was kept at -70 °C for 20 min. The mixture was extracted with dichloromethane, and the organic phases were combined. The organic phases were washed once each with purified water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a crude yellow oily substance. The crude substance was purified by column chromatography (PE / EA = 4:1) to obtain a white solid, yield: 66%. 1 H NMR(600MHz,Chloroform-d)δ7.72(td,J=7.4,2.2Hz,1H),7.64–7.59(m,1H),7.56–7.51(m,1H),5.37(s,1H),4.88(d,J=3.6Hz,1H),4.59(dd,J=12.6,3 .4Hz,1H),4.24–4.20(m,2H),4.15–4.01(m,4H),3.96–3.73(m,4H),3.63(d ,J=36.8Hz,2H),3.00(s,3H),2.36(d,J=10.2Hz,2H),2.14(d,J=8.2Hz,2H); 13CNMR(150MHz,Chloroform-d)δ168.9,167.2,165.5,164.6,163.5,159.9,158.3,132.3,128.5,120.3 ,120.1,116.8,116.1,86.3,66.2,62.3,57.2,46.4,45.5,41.7,40.7,40.5,27.5,22.0.HRMS(ESI)m / z calculated for C 24 H 25 ClFN7O2[M+H] + 498.1814, found 498.1796

[0054] Example 4: (S)-1-(4-(6-(3-methoxynaphthyl-1-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (4)

[0055] Intermediate 4,6-dichloro-2-methylthiopyrimidine (800 mg, 4.10 mmol, 1.0 eq.) and N-Boc piperazine (801 mg, 4.31 mmol, 1.05 eq.) were added sequentially to dry dichloromethane (25 mL), and the mixture was cooled to 0 °C. Triethylamine (829 mg, 8.21 mmol, 2.0 eq.) was slowly added, and the reaction was carried out at room temperature for 2 h. The mixture was then cooled to 0 °C, the pH was adjusted to neutral with 1 M HCl aqueous solution, and the mixture was extracted with dichloromethane. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a white solid product in 95% yield. 1 H NMR (400MHz, Chloroform-d) δ6.19 (s, 1H), 3.64 (t, J = 5.2Hz, 4H), 3.52 (dd, J = 6.6, 4.1Hz, 4H), 2.50 (d, J = 2.0Hz, 3H), 1.49 (d, J = 1.6Hz, 9H).

[0056] Intermediate 4-(6-chloro-2-(methylthio)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (1.6 g, 3.43 mmol, 1.0 eq), 3-methoxynaphthalene-1-boronate ester (1.43 g, 5.0 mmol, 1.5 eq), and sodium carbonate solid (1.45 g, 13.6 mmol, 4.0 eq) were dissolved in a mixed solution of 1,4-dioxane and purified water (50 mL, v / v 4:1). Under nitrogen protection, tetrakis(triphenylphosphine)palladium (200 mg, 0.17 mmol, 0.05 eq) was added, and the mixture was heated to 100 °C and reacted for 4 hours. The mixture was filtered, the reaction solution was evaporated to dryness, and purified by column chromatography to give 4-(6-(3-methoxynaphthalene-1-yl)-2-(methylthio)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, a white solid, in 87% yield. 1 H NMR (400MHz, Chloroform-d) δ8.07(d,J=8.5Hz,1H),7.77(d,J=8.2Hz,1H),7.45(ddd,J=8.2,6.8,1.2Hz,1H),7.33(ddd,J=8.3,6.8,1.3Hz,1H ),7.27(d,J=2.5Hz,1H),7.20(d,J=2.6Hz,1H),6.43(s,1H),3.95(s,3H),3.70(s,4H),3.54(dd,J=6.7,3.9Hz,4H),2.55(s,3H),1.49(s,9H).

[0057] The intermediate 4-(6-(3-methoxynaphthyl-1-yl)-2-(methylthio)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (2.15 g, 4.61 mmol, 1.0 eq) was dissolved in 60 mL of dichloromethane, and m-chloroperoxybenzoic acid (mCPBA, 1.6 g, 9.24 mmol, 2.0 eq) was added. The mixture was reacted at room temperature for 5 minutes. After the reaction was complete, 20 mL of ice water was added, and the reaction solution was extracted with dichloromethane. The organic phases were combined, washed once with salt, dried over anhydrous sodium sulfate, and evaporated to dryness to give a white solid with a yield of 80%. 1HNMR(400MHz,Chloroform-d)δ7.96–7.87(m,1H),7.73(dd,J=8.3,4.7Hz,1H),7.41(dddd,J=8.2,6.8,5.3,1.2Hz,1H),7.29(dddd,J=8.3,6.8,5.0,1.3Hz,1H ),7.21(dd,J=2.6,0.9Hz,1H),7.19(s,1H),7.17(d,J=2.6Hz,1H),3.89(d,J=2 .6Hz,3H),3.81–3.63(m,4H),3.51(t,J=5.3Hz,4H),2.90(s,3H),1.49(s,9H).

[0058] Intermediate 4-(6-(3-methoxynaphthyl-1-yl)-2-(methanesulfonyl)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (450 mg, 0.90 mmol, 1.0 eq) was added to dry tetrahydrofuran (16 mL), cooled to -20 °C, and potassium tert-butoxide (200 mg, 1.78 mmol, 2.0 eq) was slowly added, followed by (S)-(-)-1-methyl-2-pyrrolidineethanol (311 mg, 1.47 mmol, 2.7 eq). After 2 h, the solution was dissolved in 1 M... The pH was adjusted to neutral with aqueous HCl solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 4-(6-(3-methoxynaphthyl-1-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, a white solid, in 89% yield. 1 HNMR(400MHz,Chloroform-d)δ8.05(d,J=8.4Hz,1H),7.77(dd,J=8.2,1.3Hz,1H),7.45(ddd,J= 8.2,6.8,1.2Hz,1H),7.38–7.27(m,1H),7.20(d,J=2.6Hz,1H),6.43(s,1H),4.83(s,1H),4.50(d d,J=12.1,4.6Hz,1H),3.95(s,3H),3.70(s,4H),3.55(dd,J=6.7,4.0Hz,5H),3.41–3.20(m,1H), 2.80(s,3H),2.75–2.66(m,1H),2.22(q,J=6.0,4.1Hz,2H),2.01(d,J=16.3Hz,2H),1.49(s,9H).

[0059] The intermediate 4-(6-(3-methoxynaphthyl-1-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (200 mg, 0.37 mmol, 1.0 eq) was dissolved in dichloromethane (2.5 mL), and trifluoroacetic acid (0.8 mL, 911.25 mmol, 30 e.q.) was added at room temperature. The reaction was carried out at 25 °C for 30 minutes. The reaction solution was diluted with 20 mL of dichloromethane and concentrated under reduced pressure to obtain a yellow oily substance. No purification was required, and the reaction was carried out directly in the next step. The obtained oily substance was added to a dichloromethane solution (6 mL), followed by N,N-diisopropylethylamine (89 mg, 0.69 mmol, 1.5 eq). The temperature was lowered to -20 °C, and acrylic anhydride (60 mg, 0.48 mmol, 1.02 eq) was added dropwise. The reaction was maintained at -20 °C for 20 minutes. The mixture was extracted with dichloromethane, and the organic phases were combined. The organic phases were washed once each with purified water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a yellow oily crude product. The crude product was purified by column chromatography (DCM / MeOH = 10:1) to give (S)-1-(4-(6-(3-methoxynaphthyl-1-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one, which was a white solid with a yield of 89%. 1 H NMR (400MHz, DMSO-d6) δ8.08(d,J=8.5Hz,1H),7.90(d,J=8.2Hz,1H),7.50(t,J=7.5Hz,1H),7.45(d,J=2.6Hz,1H),7.36(t,J=7 .6Hz,1H),7.29(d,J=2.6Hz,1H),6.85(dd,J=16.7,10.4Hz,1H),6.71(s,1H),6.28–6.05(m,2H),5.73(dd,J=10.4,2.4Hz,1H), 4.57(dd,J=11.8,6.9Hz,1H),4.46(dd,J=11.9,4.5Hz,1H),3.93(s,3H),3.81–3.63(m,8H),3.45(s,1H),3.35(d,J=8.8Hz,1H) ,2.84(d,J=9.5Hz,1H),2.73(s,3H),2.14(dd,J=12.9,7.0Hz,1H),1.89(dq,J=15.1,7.1Hz,2H),1.76(dt,J=12.6,6.9Hz,1H); 13C NMR (101MHz, DMSO) δ166.7,164.9,164.2,156.8,138.9,135.4,131.0,130.1,128.6,128.2,127.7,127.0,126.3,12 5.9,124.5,119.8,107.9,98.9,79.7,66.3,65.7,56.8,55.9,44.9,41.5,40.6,27.6,22.4.MS(ESI)m / z:488.2[M+H] +

[0060] Example 5: 1-(4-(2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(3-methoxynaphth-1-yl)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (5)

[0061] Intermediate 4-(6-(3-methoxynaphthyl-1-yl)-2-(methanesulfonyl)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (100 mg, 0.20 mmol, 1.0 eq) was added to dry tetrahydrofuran (5 mL), cooled to -20 °C, and potassium tert-butoxide (40 mg, 0.50 mmol, 2.5 eq) was slowly added. Then (2S,7aR)-2-fluoro-1H-pyrrolidine-7a(5H)-methanol (80 mg, 1.47 mmol, 2.7 eq) was added. After 2 h, the solution was dissolved in 1 M... The pH was adjusted to neutral with aqueous HCl solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give 4-(2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(3-methoxynaphth-1-yl)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester, a white solid, yield: 95%. 1H NMR(400MHz,Chloroform-d)δ7.97(d,J=8.5Hz,1H),7.69(d,J=7.3Hz,1H),7.37(ddd,J=8.3,6.8,1.3 Hz,1H),7.30–7.23(m,1H),7.18(d,J=2.5Hz,1H),7.12(d,J=2.8Hz,1H),6.33(s,1H),5.29(d,J=52.7 Hz,1H),4.45–4.26(m,2H),3.88(d,J=4.8Hz,4H),3.61(d,J=5.8Hz,5H),3.47(dd,J=6.9,3.7Hz,5H), 3.27(t,J=15.9Hz,1H),3.03(d,J=7.6Hz,1H),2.39–2.22(m,3H),2.01(d,J=12.3Hz,3H),1.41(s,9H).

[0062] Intermediate 4-(2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(3-methoxynaphthyl-1-yl)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester (180 mg, 0.31 mmol, 1.0 eq) was dissolved in dichloromethane (2.2 mL), and trifluoroacetic acid (0.7 mL, 9.36 mmol, 30 e.q.) was added at room temperature. The reaction was carried out at 25 °C for 30 minutes. 20 mL of dichloromethane was added to dilute the reaction solution, and the solution was concentrated under reduced pressure to obtain a yellow oily substance. No purification was required, and the reaction was carried out directly in the next step. The obtained oily substance was added to a dichloromethane solution (5 mL), followed by N,N-diisopropylethylamine (68 mg, 0.52 mmol, 1.67 eq). The temperature was lowered to -20 °C, and acrylic anhydride (45 mg, 0.37 mmol, 1.20 eq) was added dropwise. The reaction was maintained at -20 °C for 20 minutes. The mixture was extracted with dichloromethane, and the organic phases were combined. The organic phases were washed once each with purified water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a yellow oily crude product. The crude product was purified by column chromatography (DCM / MeOH = 10:1) to give 1-(4-(2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(3-methoxynaphth-1-yl)pyrimidin-4-yl)piperazin-1-yl)propyl-2-en-1-one, which was a white solid with a yield of 90%. 1HNMR(400MHz, DMSO-d6)δ8.07–8.01(m,1H),7.93–7.86(m,1H),7.49(ddd,J=8.2,6.8,1.3Hz,1H),7.45(d,J=2.7Hz,1H), 7.35(ddd,J=8.3,6.8,1.4Hz,1H),7.27(d,J=2.6Hz,1H),6.85(dd,J=16.7,10.5Hz,1H),6.76(s,1H),6.16(dd,J=16.7,2 .4Hz,1H),5.73(dd,J=10.4,2.3Hz,1H),5.45–5.41(m,0.5H),5.31–5.27(m,0.5H),4.19(d,J=10.8Hz,4H),4.12(d,J=10 .6Hz,3H),3.68(dd,J=29.7,9.2Hz,8H),3.35–3.27(m,3H),2.97(t,J=7.5Hz,1H),2.27–2.06(m,3H),1.98–1.79(m,3H); 13 C NMR (101MHz, DMSO) δ167.4,164.9,164.1,156.8,139.0,135.4,131.1,130.0,128.6,128.1,127.7,126.9,126.3,12 5.9,124.5,119.8,107.8,98.7,79.7,60.2,59.9,57.1,55.8,44.9,42.4,42.2,41.5,39.4,35.8,25.3.MS(ESI)m / z 532.2[M+H] + .

[0063] Example 6: ((S)-4-(4-acryloylpiperazin-1-yl)-6-(3-methoxynaphth-1-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidine-5-carboxynitrile (6)

[0064] The synthesis of intermediate 4-(5-cyano-6-(3-methoxynaphthyl-1-yl)-2-(methylthio)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester is consistent with that of intermediate 4-(5-cyano-6-(4-cyano-2-fluorophenyl)-2-(methylthio)pyrimidin-4-yl)piperazine-1-carboxylic acid tert-butyl ester. The NMR data for this intermediate are as follows: 1HNMR(400MHz,Chloroform-d)δ7.79(d,J=8.0Hz,1H),7.68(d,J=8.4Hz,1H),7.50–7.46(m,1H),7.35–7.3 2(m,1H),7.28–7.26(m,2H),4.04–4.01(m,4H),3.95(s,3H),3.66–3.56(m,4H),2.54(s,3H),1.49(s,9H).

[0065] Intermediate tert-butyl 4-(5-cyano-6-(3-methoxynaphthyl-1-yl)-2-(methylthio)pyrimidin-4-yl)piperazine-1-carboxylate (240 mg, 0.49 mmol, 1.0 eq) was added to dry tetrahydrofuran (5 mL), cooled to -10 °C, and sodium hydride solid (118 mg, 2.94 mmol, 60%, 6.0 eq) was slowly added. The mixture was cooled to -78 °C, and (S)-(-)-1-methyl-2-pyrrolidineethanol (170 mg, 1.47 mmol, 3.0 eq) was added. The pH was adjusted to neutral with 1 M HCl aqueous solution at -30 °C, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give a white solid in 80% yield. 1 H NMR (600MHz, DMSO-d6) δ7.97(d,J=8.4Hz,1H),7.75(d,J=8.4Hz,1H),7.59(d,J=2.4Hz,1H),7.56(ddd,J=8.4,6.8,1.2Hz,1H),7. 47(d,J=2.6Hz,1H),7.40(ddd,J=8.4,6.8,1.2Hz,1H),4.07(t,J=4.8Hz,4H),3.95(s,3H),3.59(s,4H),3.39(s,3H),1.44(s,9H).

[0066] The synthesis of (S)-4-(4-acryloylpiperazin-1-yl)-6-(3-methoxynaphth-1-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidin-5-carboxynitrile (6) is consistent with that of (S)-1-(4-(6-(3-methoxynaphth-1-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidin-4-yl)piperazin-1-yl)prop-2-en-1-one (4), and the NMR and mass spectrometry data are as follows: 1HNMR(600MHz,DMSO-d6)δ7.93(dd,J=8.4,4.2Hz,1H),7.74–7.69(m,1H),7.56–7.49(m,2H),7.41–7.30(m,2 H),6.90–6.78(m,1H),6.21–6.11(m,1H),5.75–5.72(m,1H),4.92–4.65(m,1H),4.34(dd,J=10.8,4.8Hz,1H ),4.19(dd,J=10.8,6.0Hz,1H),4.11–3.97(m,4H),3.93(s,3H),3.84–3.81(m,4H),3.00–2.89(m,1H),2.70 –2.55(m,1H),2.32(s,2H),2.18(q,J=8.6Hz,1H),2.11–1.98(m,1H),1.95–1.89(m,1H),1.74–1.55(m,2H); 13 C NMR(150MHz,DMSO-d6)δ174.2,164.9,164.3,163.8,163.4,156.5,136.5,135.2,128.5,128.3,127.8,126.0,125.4,124 .9,120.1,117.8,108.6,85.6,70.3,63.6,57.4,55.9,46.8,46.1,45.8,44.5,41.6,28.8,23.1; MS(ESI)m / z:513.4[M+H] + ;

[0067] Example 7: 4-(4-Acryloylpiperazin-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(3-methoxynaphth-1-yl)pyrimidin-5-carboxynitrile (7)

[0068] The synthesis method is the same as in Example 5; only the data for intermediates and preferred compounds are shown here:

[0069] tert-Butyl 4-(5-cyano-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(3-methoxynaphth-1-yl)pyrimidin-4-yl)piperazine-1-carboxylic acid ester: 1H NMR(400MHz,Chloroform-d)δ7.93(d,J=8.2Hz,1H),7.69(d,J=7.4Hz,1H),7.47(ddd,J=8.2,6.8, 1.4Hz,1H),7.30–7.23(m,1H),7.18(d,J=2.5Hz,1H),7.12(d,J=2.8Hz,1H),5.35(d,J=48.8Hz,1H) ,4.46–4.08(m,2H),3.88(d,J=4.5Hz,5H),3.61(d,J=5.8Hz,4H),3.42(dd,J=6.8,3.8Hz,5H),3.2 6(t,J=15.8Hz,1H),3.04(d,J=7.8Hz,1H),2.39–2.22(m,3H),1.98(d,J=12.3Hz,3H),1.50(s,9H).

[0070] 4-(4-Acryloylpiperazin-1-yl)-2-(((2S,7aR)-2-fluorotetrahydro-1H-pyrrolidine-7a(5H)-yl)methoxy)-6-(3-methoxynaphthyl-1-yl)pyrimidin-5-carboxynitrile(7): 1 H NMR (400MHz, DMSO-d6) δ7.98–7.81(m,1H),7.72–7.55(m,1H),7.36(m,1H),7.45(d,J=2.6Hz,1H ),7.22(m,1H),7.12(d,J=2.6Hz,1H),6.62(dd,J=16.8,10.4Hz,1H),6.05(dd,J=16.8,2.4Hz,1H ),5.64(dd,J=10.4,2.4Hz,1H),5.44–5.29(m,1H),4.17(d,J=10.6Hz,4H),4.10(d,J=10.6Hz,3 H),3.65(m,8H),3.35–3.27(m,3H),2.97(t,J=7.5Hz,1H),2.26–2.06(m,3H),1.95–1.70(m,3H); 13 CNMR(101MHz,DMSO)δ167.2,164.8,164.0,156.5,138.9,135.6,131.1,130.1,128.6,128.1,127.7,126.9,126.3,12 5.9,124.5,121.3,119.8,107.8,79.7,60.2,59.7,57.0,55.8,44.9,42.7,42.2,41.5,39.2,35.6,26.0.MS(ESI)m / z 557.2[M+H]+ .

[0071] Example 8: (S)-4-(2-Acryloyl-2,6-diazaspiro[3.4]octane-6-yl)-6-(3-methoxynaphth-1-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidine-5-carboxynitrile

[0072] The intermediate 6-(6-chloro-5-cyano-2-(methylthio)pyrimidin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester was synthesized in the same manner as tert-butyl 4-(6-chloro-2-(methylthio)pyrimidin-4-yl)piperazine-1-carboxylic acid ester, except that 2,6-diazaspiro[3.4]octane-2-carboxylic acid tert-butyl ester was used to replace N-Boc piperazine. The intermediate was obtained by nucleophilic substitution reaction and was a white solid with a yield of 89%. 1 HNMR(400MHz,Chloroform-d)δ4.16–3.73(m,8H),2.51(s,3H),2.23(s,2H),1.45(s,9H).

[0073] The intermediate tert-butyl 6-(5-cyano-6-(3-methoxy-2-(methylthio)naphth-1-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate was subjected to the same NMR spectra as tert-butyl 4-(6-(3-methoxynaphth-1-yl)-2-(methylthio)pyrimidin-4-yl)piperazine-1-carboxylate, yielding a white solid in 73% yield. 1 HNMR(400MHz,Chloroform-d)δ7.78(d,J=8.4Hz,1H),7.66(d,J=8.4Hz,1H),7.53–7.41(m,1H),7.36–7.32(m,1H),7.26 (s,2H),3.98(d,J=11.2Hz,4H),3.95(s,3H),3.90(d,J=8.8Hz,2H),2.54(s,3H),2.23(s,2H),1.59(s,2H),1.46(s,9H).

[0074] The intermediate tert-butyl 6-(5-cyano-6-(3-methoxy-2-(methanesulfonyl)naphth-1-yl)pyrimidin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate was synthesized in the same manner as tert-butyl 4-(6-(3-methoxynaphth-1-yl)-2-(methanesulfonyl)pyrimidin-4-yl)piperazine-1-carboxylate, yielding a white solid in 82% yield. 1H NMR(400MHz,Chloroform-d)δ7.78(d,J=8.0Hz,1H),7.66(d,J=8.4Hz,1H),7.46(t,J=7.6Hz,1H),7.3 3(t,J=8.0Hz,1H),7.29–7.26m,2H),4.14–3.83(m,8H),2.54(s,2H),2.23(s,3H),1.49–1.51(m,12H).

[0075] The synthesis method of (S)-4-(2-acryloyl-2,6-diazaspiro[3.4]octane-6-yl)-6-(3-methoxynaphth-1-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidine-5-carboxynitrile is the same as that of the preferred compound in Example 3. 1 H NMR(600MHz, DMSO-d6)δ7.92(d,J=8.4Hz,1H),7.66(d,J=9.0Hz,1H),7.53–7.50(m,2H),7.36(t ,J=7.8Hz,1H),7.26(s,1H),6.39–6.18(m,1H),6.16–6.05(m,1H),5.81–5.67(m,1H),4.40–4.27 (m,2H),4.22–4.16(m,2H),3.99(d,J=10.2Hz,1H),3.93(s,3H),3.01–2.89(m,1H),2.68–2.55( m,1H),2.34(s,3H),2.25–2.15(m,3H),2.07–1.88(m,2H),1.69–1.59(m,3H),1.25–1.18(m,1H). 13 C NMR(150MHz,DMSO-d6)δ173.5,165.1,164.2,161.0,156.5,136.7,135.1,127.7,127.4,127.2,126.9,125.9,125.3,124 .8,119.7,118.0,108.3,84.8,79.6,69.9,63.7,58.8,57.3,56.5,55.9,47.9,41.6,28.7,23.0; MS(ESI)m / z:561.3[M+H] + .

[0076] Example 9: (S)-4-(4-acryloylpiperazin-1-yl)-6-(8-methylnaphthyl-1-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidin-5-carboxynitrile

[0077] The intermediate tert-butyl 4-(6-chloro-5-cyano-2-(methylthio)pyrimidin-4-yl)piperazine-1-carboxylate (1.0 g, 2.7 mmol 1.0 eq) was added to 18 mL of DCM, and trifluoroacetic acid (5.9 mL, 81 mmol, 30 eq) was added dropwise under ice bath conditions. The reaction was carried out at 25 °C for 30 minutes. 20 mL of dichloromethane was added to dilute the reaction solution, and the solution was concentrated under reduced pressure to obtain a yellow oily substance. No purification was required, and the reaction was carried out directly in the next step. The obtained oily substance was added to a dichloromethane solution (30 mL), followed by N,N-diisopropylethylamine (699 mg, 5.42 mmol, 2.0 eq). The temperature was lowered to -20 °C, and acrylic anhydride (273 mg, 2.17 mmol, 0.8 eq) was added dropwise. The reaction was maintained at -20 °C for 20 minutes. The mixture was extracted with dichloromethane, and the organic phases were combined. The organic phases were washed once each with purified water and saturated brine, dried over anhydrous sodium sulfate, and evaporated to dryness to obtain a yellow oily crude product. The crude product was purified by column chromatography (DCM / MeOH = 10:1) to give 4-(4-acryloylpiperazin-1-yl)-6-chloro-2-(methylthio)pyrimidin-5-carboxynitrile as a white solid, with a yield of 92%. 1 HNMR(400MHz,Chloroform-d)δ6.58(dd,J=16.8,10.5Hz,1H),6.36(dd,J=16.8,1.9Hz,1H),5.77(dd,J=10.5,1.8Hz,1H),3.83–3.62(m,9H),2.50(s,3H).

[0078] The intermediate 4-(4-acryloylpiperazin-1-yl)-6-chloro-2-(methylthio)pyrimidin-5-carboxylonitrile (300 mg, 0.92 mmol, 1.0 eq) was dissolved in 9 mL of dichloromethane, and m-chloroperoxybenzoic acid (mCPBA, 321 mg, 1.86 mmol, 2.0 eq) was added. The mixture was reacted at room temperature for 5 minutes. After the reaction was complete, 9 mL of ice water was added, and the reaction solution was extracted with dichloromethane. The organic phases were combined, washed once with salt, dried over anhydrous sodium sulfate, and evaporated to dryness to give 4-(4-acryloylpiperazin-1-yl)-6-chloro-2-(methanesulfonyl)pyrimidin-5-carboxylonitrile as a white solid with a yield of 89%. 1 H NMR (400MHz, Chloroform-d) δ6.58(dd,J=16.7,10.5Hz,1H),6.37(dd,J=16.8,1.8Hz,1H),5.65(dd,J=10.6,1.8Hz,1H),3.83–3.62(m,9H),3.32(s,3H).

[0079] Intermediate 4-(4-acryloylpiperazin-1-yl)-6-chloro-2-(methanesulfonyl)pyrimidin-5-carboxylon (400 mg, 1.13 mmol, 1.0 eq) was added to dry tetrahydrofuran (16 mL), cooled to -20 °C, and 60% sodium hydride (180 mg, 4.5 mmol, 4.0 eq) was slowly added. Then (S)-(-)-1-methyl-2-pyrrolidineethanol (259 mg, 2.25 mmol, 2.0 eq) was added. After 2 h, the pH was adjusted to neutral with 1 M HCl aqueous solution, and the mixture was extracted with ethyl acetate. The organic phases were combined, washed once with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography to give (R)-4-(4-acryloylpiperazin-1-yl)-6-chloro-2-((1-methylpyrrolidine-2-yl)methoxy)pyrimidin-5-carboxylon as a white solid, yield: 59%. 1 H NMR(400MHz,Chloroform-d)δ4.29(dd,J=10.7,5.1Hz,1H),4.09(dd,J=10.7,6.6Hz,1H),3.55(s,4H),3.43(dd,J=6.8,3.9Hz,4H),3 .03(d,J=8.2Hz,1H),2.61(s,1H),2.42(s,3H),2.23(d,J=8.7Hz,1H),1.97(dd,J=12.0,7.4Hz,1H),1.85–1.60(m,3H),1.42(s,9H).

[0080] Intermediate (R)-4-(4-acryloylpiperazin-1-yl)-6-chloro-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidin-5-carboxynitrile (200 mg, 0.51 mmol, 1.0 eq), 8-methylnaphthalene-1-ylboronic acid ester (346 mg, 1.28 mmol, 2.5 eq), and sodium carbonate solid (163 mg, 1.53 mmol, 3.0 eq) were dissolved in a mixed solution of 1,4-dioxane and purified water (10 mL, v / v). Under nitrogen protection, tetrakis(triphenylphosphine) palladium (59 mg, 0.05 mmol, 0.1 eq) was added, and the mixture was heated to 100 °C and reacted for 4 hours. The mixture was filtered, the reaction solution was evaporated to dryness, and purified by column chromatography to give (S)-4-(4-acryloylpiperazin-1-yl)-6-(8-methylnaphthyl-1-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidine-5-carboxynitrile, as a white solid with a yield of 76%. 1H NMR (400MHz, DMSO-d6) δ8.12–8.03(m,1H),7.92(d,J=8.4Hz,1H),7.65–7.49(m,4 H),6.90–6.82(m,1H),6.18(d,J=16.8Hz,1H),5.75(s,1H),4.47–4.38(m,1H),4.3 0(dd,J=11.4,5.8Hz,2H),4.04(d,J=19.4Hz,5H),3.78(d,J=34.6Hz,4H),3.65(s, 1H),2.91–2.80(m,1H),2.44(s,3H),2.25(s,3H),2.11–1.94(m,1H),1.68(m,3H); 13 C NMR(150MHz,DMSO-d6)δ178.8,167.9,164.2,163.8,163.4,156.5,136.5,135.1,128.5,128.3,127.4,126.8,125.6,125 .0,124.7,120.1,117.8,85.7,64.257.2,53.8,46.9,46.1,46.0,44.5,41.3,28.4,23.3;22.8.MS(ESI)m / z:532.2[M+H] + ;

[0081] Example 10: (S)-4-(4-acryloylpiperazin-1-yl)-6-(8-methoxynaphth-1-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidin-5-carboxynitrile

[0082] Intermediate (R)-4-(4-acryloylpiperazin-1-yl)-6-chloro-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidin-5-carboxynitrile (300 mg, 0.51 mmol, 1.0 eq), 8-methoxynaphthalene-1-ylboronic acid ester (549 mg, 1.28 mmol, 2.5 eq), and sodium carbonate solid (244 mg, 2.31 mmol, 3.0 eq) were dissolved in a mixed solution of 1,4-dioxane and purified water (14 mL, v / v). Under nitrogen protection, tetrakis(triphenylphosphine) palladium (88 mg, 0.08 mmol, 0.1 eq) was added, and the mixture was heated to 100 °C and reacted for 4 hours. The mixture was filtered, the reaction solution was evaporated to dryness, and purified by column chromatography to give (S)-4-(4-acryloylpiperazin-1-yl)-6-(8-methylnaphthyl-1-yl)-2-((1-methylpyrrolidone-2-yl)methoxy)pyrimidine-5-carboxynitrile, as a white solid with a yield of 71%. 1HNMR(400MHz,DMSO-d6)δ8.02(d,J=8.7Hz,1H),7.73(d,J=8.6Hz,1H),7.50–7.42(m,2H),7.35–7 .26(m,2H),6.82(dd,J=16.6,10.4Hz,1H),6.22–6.01(m,2H),5.71(dd,J=10.4,2.4Hz,1H),4.59 (dd,J=11.8,4.4Hz,1H),4.49(dd,J=11.9,4.5Hz,1H),3.81–3.60(m,8H),3.45(s,4H),3.35(d,J =8.8Hz,1H),2.84(d,J=9.5Hz,1H),2.73(s,3H),2.14(dd,J=12.9,7.0Hz,1H),1.91–1.79(m,2H); 13 C NMR (101MHz, DMSO) δ167.4,165.2,164.2,156.5,138.0,135.2,130.6,130.1,128.5,128.0,127.6,127.0,126.5,125.7 ,124.1,121.3,119.0,107.9,66.3,65.7,60.5,56.8,55.9,46.0,44.7,41.4,40.5,28.2,22.1.MS(ESI)m / z:513.2[M+H] +

[0083] Example 11: Anti-cell proliferation activity of compounds 1–10

[0084] The in vitro cytotoxic activity of the compound against the KRAS-G12C-overexpressing cell lines NCI-H23 or NCI-H358 (non-small cell lung cancer cells) was determined by the MTT assay, with the KRAS-G12C inhibitor ARS1620 used as a positive control. The results are shown in Table 1.

[0085] MTT assay: NCI-H23 or NCI-H358 cells in logarithmic growth phase (5 × 10⁻⁶ cells) were subjected to MTT assay. 6 Cells per well were added to a 96-well plate containing 10% FBS and incubated for 24 hours at 37°C, 5% CO2. Different concentrations of the drug were then added, and the plate was incubated for 72 hours. MTT solution (5 mg / mL) was added, and the plate was incubated for 4 hours. The culture medium was discarded, DMSO was added, and the plate was shaken well. The absorbance was measured at 490 nm using a microplate reader. The IC50 was calculated using GraphPad Prism Software version 5.02. 50 value.

[0086] Example 12: Inhibitory activity of compounds 1–10 against KRAS-G12C protein

[0087] The TR-FRET method was used, and the KRAS-G12C inhibitor ARS1620 was selected as the positive compound. The in vitro inhibitory activity of pyrimidine compounds 1–7 on KRAS-G12C was studied. The experimental results are shown in Table 1.

[0088] TR-FRET assay: Compound solutions of different concentration gradients were prepared and added to a 384-well Source plate. An equal volume of positive control compound and DMSO were added. Then, buffer and protein solution were prepared; centrifuged and incubated; the prepared peptide solution was added and centrifuged again; subsequently, the test solution was added and centrifuged and incubated again. After the compounds and enzyme proteins had bound, the IC50 was calculated using GraphPadPrism 5. 50 value.

[0089] Table 1. Inhibitory activity of compounds 1-12 against KRAS-G12C protein and its mutant cells.

[0090]

[0091]

[0092] a. The mean of the two experiments

[0093] b. The average of the three experiments, over a period of 72 hours.

[0094] Table 1 shows that the novel pyrimidine compounds of this invention exhibit potent inhibitory activity against KARS-G12C protein and its mutant cell lines. Most compounds showed superior enzyme-inhibiting and anti-proliferative activities compared to the positive control drug ARS1620. In particular, compounds 5 and 7 showed significantly higher IC50 values ​​against non-small cell lung cancer cells NCI-H23 and NCI-H358. 50 The values ​​were all less than 0.1 μM, and the anti-proliferative activity was nearly 500 times higher than that of ARS1620, which was significantly better than that of ARS1620.

[0095] Comparative Example

[0096] Comparison of therapeutic effects

[0097] This invention discloses a novel class of pyrimidine antitumor compounds. Compared to the positive control drug ARS1620, compounds 5 and 7 exhibit nearly 300-fold increased antiproliferative activity against non-small cell lung cancer (NSCLC) NCI-H23 and NCI-H358 cells. The results indicate that the compounds of this invention significantly enhance antiproliferative activity against NSCLC. The preferred embodiments of this invention have been described in detail above. However, this invention is not limited to the specific details of the above embodiments. Within the scope of the inventive concept, various equivalent modifications can be made to the technical solutions of this invention. To avoid unnecessary repetition, various possible combinations will not be described separately. Any modifications, equivalent substitutions, or improvements made within the scope of the inventive concept are included within the protection scope of this invention.

Claims

1.The present application provides a compound of structural formula as shown in formula I or a pharmaceutically acceptable salt thereof: wherein: R 1 selected from hydrogen, C 1-6 alkyl, halogen or cyano; R 2 selected from hydrogen, C 3-6 heterocyclyl, C 3-6 heterocycloalkyloxy, or C 3-6 heterocycloalkylamino; Ring L is a saturated or partially saturated monocyclic, bridged cyclic, or spirocyclic ring of 4-12 atoms, wherein the saturated or partially saturated monocyclic ring can optionally additionally be substituted with one or more R 3 substituents, wherein R 3 is selected from: hydrogen, cyano, C 1-6 alkyl, C 1-6 alkoxy, or C 3-6 cycloalkyl; Ar is selected from C 6-10 aryl or C 5-10 heteroaryl; R 4 selected from C 1-4 alkenyl, C 1-6 haloalkyl, C 5-10 heteroaryl or C 3-6 halocycloalkyl. 2.The pyrimidine compound and the pharmaceutically acceptable salt thereof according to claim 1, characterized in that: In a further preferred embodiment of the present application, R 1 is preferably methyl, cyano. In a further preferred embodiment of the application, R 2 selected from (S)-2-(1-oxyl) methyl)-N-methylpyrrolidinyl or (2S,7aR)-7a-((1-oxyl)methyl))-2-fluorohexahydro-1 H-pyrrolizinyl; In further preferred embodiments of the application, ring L is selected from the group consisting of piperazine, monosubstituted piperazine, polysubstituted piperazine, spirocyclic, and the like. In further preferred embodiments of the application, R 3 is preferably methyl. In a further preferred embodiment of the present application, Ar is phenyl, 2-fluoro-4-nitrophenyl, 2-fluoro-4-cyanophenyl, 2,6-dimethylphenyl, 4-chlorophenyl, 2-fluoro-6-methoxyphenyl, 1-naphthyl or 1-(4-chlorophenyl)pyrazolyl-3. In a further preferred embodiment of the application, R 4 is vinyl, chloromethyl. 3.The pyrimidine derivative or a pharmaceutically acceptable salt thereof according to claims 1-2 for use in the preparation of a KRAS-G12C inhibitor anticancer drug. 4.The pyrimidine derivative or a pharmaceutically acceptable salt thereof according to claims 1-2 for use in the preparation of a non-small cell lung cancer drug. 5.The pyrimidine derivative or a pharmaceutically acceptable salt thereof according to claims 1-2 for use in the preparation of a pancreatic cancer drug.

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